CN101918405B - 13a-(s) desoxytylophorinine derivatives, preparation method, pharmaceutical compositon and use thereof - Google Patents

13a-(s) desoxytylophorinine derivatives, preparation method, pharmaceutical compositon and use thereof Download PDF

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CN101918405B
CN101918405B CN2010800007867A CN201080000786A CN101918405B CN 101918405 B CN101918405 B CN 101918405B CN 2010800007867 A CN2010800007867 A CN 2010800007867A CN 201080000786 A CN201080000786 A CN 201080000786A CN 101918405 B CN101918405 B CN 101918405B
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meo
trimethoxy
luxuriant
indoles
fragrance
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CN101918405A (en
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庾石山
陈晓光
吕海宁
刘振佳
许嵩
马双刚
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Institute of Materia Medica of CAMS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Abstract

13a-(S) desoxytylophorinine derivatives represented by general formula (I), their preparation method, pharmaceutical composition containing them and use thereof in the manufacture of medicaments for preventing and/or treating cancer and/or inflammation are disclosed.

Description

13a-(S) deoxidation tylophorinine derivative, its method for making and pharmaceutical composition and purposes
Technical field
The present invention relates to a kind of 13a-(S) deoxidation tylophorinine derivative, the preparation method of this compounds, the pharmaceutical composition and this compounds that contain them prevent and/or treat application in the medicine of cancer and/or inflammatory disease in preparation.
Background technology
Phenanthroindolizididerivative pyridine alkaloid mainly is distributed in the Asclepiadaceae Tylophora plant, has multiple pharmacologically active, and wherein antitumor action and anti-inflammatory action attract people's attention.Find that in the antitumor screening of American National cancer research institute (NCI) this Alkaloid has significant effect for 60 kinds of tumor cell lines, half growth-inhibiting dosage (GI 50) 10 -8M level, and for malignant tumour, such as melanoma and lung carcinoma cell good selectivity is arranged, effective for the resistance cancerous cell line, and do not have cross resistance with other anticarcinogen.
(+)-13a-(S)-deoxidation tylophorinine (has been applied for the compound patent, application number 200610076298.X) be to be located away from phenanthroindolizididerivative pyridine alkaloid in three fens pellets of Asclepiadaceae Tylophora plant, has very strong anti-tumor activity, for the IC of human oral cavity epithelial cancer cells KB and human colon cancer cell HCT-8 50Be respectively 0.13 μ M and 0.26 μ M.
To studies show that of the mechanism of action of this compounds anti-tumor activity, it is for the DNA of cell and synthetic all influential (the Bioorg Med Chem Lett.2006 of RNA and protein, 16:4300-4304.), but further molecular pharmacology studies show that, the mechanism of action of the various antitumour drugs of its mechanism of action and clinical application is completely different, this compounds has optionally potent restraining effect for the NF-κ B signal path that influences the rna transcription process, and this action intensity and mutual corresponding [the Mol Cancer Ther.2006 of the intensity of its cytotoxic activity, 5 (10): 2484-2493.], but concrete action target spot also research among.
The anti-inflammatory action of this compounds is also relevant with its inhibition NF-κ B signal path, and closely related [the Mol Pharm.2006 of effect of this effect and the MEKK1 of its blocking-up NF-κ B signal path upstream, 69 (3): 749-758.], but concrete action target spot is still unknown.
Up to now, the definite action target spot of this compounds also determines, discloses this brand-new target spot, the brand-new mechanism of action is significant for cancer and other treatment of diseases.
Summary of the invention
The technical problem to be solved in the present invention is to provide hydrate, ester or the prodrug of acceptable salt, salt on general formula (I) compound and the pharmacodynamics thereof.
The another technical problem that the present invention will solve is to provide the method for hydrate, ester or the prodrug of acceptable salt, salt on preparation general formula (I) compound and the pharmacodynamics thereof.
The another technical problem that the present invention will solve is to provide a kind of pharmaceutical composition, and it comprises hydrate, ester or prodrug and pharmaceutical salts and pharmaceutical carrier and/or the vehicle of acceptable salt, salt at least one general formula (I) compound and the pharmacodynamics thereof.
Hydrate, ester or the prodrug that the technical problem again that the present invention will solve is to provide acceptable salt, salt on general formula (I) compound and the pharmacodynamics thereof is for the preparation of the application that prevents and/or treats in cancer and/or the inflammation medicine.
For solving the problems of the technologies described above, the technical solution used in the present invention is:
According to the present invention, deoxidation tylophorinine compound is shown in general formula (I):
Figure GPA00001137007000021
Wherein, R is selected from-NR 1R 2Or-OR 3
R 1And R 2Independently be selected from hydrogen, replacement or unsubstituted C 1-10Straight chain and branched-chain alkyl, replacement or unsubstituted C 3-7Cycloalkyl, replacement or unsubstituted phenyl, replacement or unsubstituted aromatic heterocyclic;-NR 1R 2Constitute five yuan, hexa-atomic or seven yuan contain 1～3 heteroatomic saturated heterocyclic;
R 3Be selected from and replace or unsubstituted C 1-10Straight chain and branched-chain alkyl, replacement or unsubstituted C 3-7Cycloalkyl, replacement or unsubstituted phenyl, replacement or unsubstituted aromatic heterocyclic;
Substituting group is selected from hydroxyl, sulfydryl, amino-NH 2, C 1-6Amido, phenyl or aromatic heterocyclic that alkyl replaces.
According to the present invention, the compound shown in the preferred general formula (I) comprises, but is not limited to the compound shown in the general formula (IA):
Wherein, R 1And R 2Independently be selected from hydrogen, replacement or unsubstituted C 1-6Straight chain and branched-chain alkyl, replacement or unsubstituted C 3-7Cycloalkyl; Substituting group is selected from hydroxyl, sulfydryl, amino-NH 2, C 1-3Amido, phenyl or aromatic heterocyclic that alkyl replaces.
According to the present invention, the compound shown in the preferred general formula (IA) comprises, but is not limited to the compound shown in the general formula (IAa):
Figure GPA00001137007000032
Wherein, R 1Be selected from replacement or unsubstituted methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, substituting group is selected from hydroxyl, sulfydryl, amino-NH 2Or C 1-3The amido that alkyl replaces.
According to the present invention, the compound shown in the preferred general formula (IA) comprises, but is not limited to the compound shown in the general formula (IAb):
Wherein, R 1Be selected from replacement or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, benzyl, substituting group is selected from hydroxyl, sulfydryl, amino-NH 2Or C 1-3The amido that alkyl replaces.
According to the present invention, the compound shown in the preferred general formula (IA) comprises, but is not limited to the compound shown in the general formula (IAc):
Figure GPA00001137007000041
Wherein, R 1Be selected from the C of replacement 1-4Straight chain and branched-chain alkyl; Substituting group is selected from phenyl, furyl, imidazolyl, pyridyl, thienyl, pyrryl, thiazolyl, pyrimidyl.
According to the present invention, the compound shown in the preferred general formula (I) comprises, but is not limited to the compound shown in the general formula (IB):
Figure GPA00001137007000042
Wherein, R 3Be selected from and replace or unsubstituted C 1-6Straight chain and branched-chain alkyl, replacement or unsubstituted C 3-7Cycloalkyl; Substituting group is selected from hydroxyl, sulfydryl, amino-NH 2, C 1-3Amido, phenyl or aromatic heterocyclic that alkyl replaces.
According to the present invention, the compound shown in the preferred general formula (IB) comprises, but is not limited to the compound shown in the general formula (IBa):
Figure GPA00001137007000043
Wherein, R 3Be selected from replacement or unsubstituted methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, substituting group is selected from hydroxyl, sulfydryl, amino-NH 2Or C 1-3The amido that alkyl replaces.
According to the present invention, the compound shown in the preferred general formula (IB) comprises, but is not limited to the compound shown in the general formula (IBb):
Figure GPA00001137007000051
Wherein, R 3Be selected from replacement or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, substituting group is selected from hydroxyl, sulfydryl, amino-NH 2Or C 1-3The amido that alkyl replaces.
According to the present invention, the compound shown in the preferred general formula (IB) comprises, but is not limited to the compound shown in the general formula (IBc):
Figure GPA00001137007000052
Wherein, R 3Be selected from the C of replacement 1-4Straight chain and branched-chain alkyl; Substituting group is selected from phenyl, furyl, imidazolyl, pyridyl, thienyl, pyrryl, thiazolyl, pyrimidyl.
C in the present invention 1-10Straight chain and branched-chain alkyl are selected from: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, 2-methyl butyl, amyl group, 1-methyl butyl, 3-methyl butyl, 1-ethyl propyl, hexyl, 1-methyl amyl, 2-methyl amyl, 3-methyl amyl, 4-methyl amyl, 1-ethyl-butyl, 2-ethyl-butyl, heptyl, octyl group, nine alkyl, ten alkyl etc.; C 3-7Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or suberyl; Aromatic heterocyclic is selected from furyl, imidazolyl, pyridyl, thienyl, pyrryl, thiazolyl, pyrimidyl etc.
According to the present invention, preferred compound include but not limited to following compound:
Figure GPA00001137007000053
The method for preparing The compounds of this invention also is provided according to the present invention.
1. working as R is-NR 1R 2The time:
The 14-position carbonyl of formula 7 is generated substituted amido (formula 10) with replacing amine through reductive amination process, the non-corresponding body isomer of chromatographic separation, the 11-position carbonyl that reduces respectively gets compound shown in the general formula (I);
Figure GPA00001137007000071
(a) catalyzer that the 14-position carbonyl of formula 7 is carried out reduction amination is titanium tetrachloride, the mol ratio of titanium tetrachloride and formula 7 compounds is preferably 1: 1～and 4, most preferably be 1: 2; Reaction solvent is preferably methylene dichloride; Preferred-20～-40 ℃ of the temperature of reaction beginning more preferably-20～-30 ℃, most preferably-20 ℃, keeps rising to room temperature reaction after 1～2 hour room temperature reaction 22～36 hours, preferred 24～28 hours, most preferably 24 hours.
(b) product that step (a) is obtained filters, and the solution evaporate to dryness is obtained imine intermediate, and preferably sodium borohydride reduces to imine intermediate, obtains the diastereomer product.
(c) it is 50: 1 methylene dichloride and methanol solution that formula 10 compounds that reaction obtained adopt silica gel column chromatography to separate to obtain diastereomer, moving phase to be preferably volume ratio.
(d) non-corresponding body isomer is reduced respectively, preferred reductive agent is tetrahydrochysene lithium aluminium, and reaction solvent is preferably tetrahydrofuran (THF).
2. working as R is-OR 3The time:
The 14-position carbonyl reduction of formula 7 is become hydroxyl (formula 8), 14-position hydroxyl and haloalkane generation substitution reaction are generated alkoxyl group (formula 11), the chromatographic separation diastereomer, the 11-position carbonyl that reduces respectively gets compound shown in the general formula (I):
Figure GPA00001137007000072
Figure GPA00001137007000081
(a) be that the reductive agent of hydroxyl is preferably sodium borohydride with the 14-position carbonyl reduction of formula 7, reaction solvent is preferably the mixed solution of dichloride alkane and methyl alcohol; Temperature of reaction is preferably room temperature condition, and the reaction times is preferably 20～40 minutes, more preferably 25～35 minutes; In reaction system, add saturated ammonium chloride solution with termination reaction.
(b) be sodium hydride with the 14-position hydroxyl of formula 8 and the catalyzer of haloalkane generation substitution reaction, reaction solvent is preferably tetrahydrofuran (THF); Temperature of reaction is preferably room temperature, and the reaction times is preferably 22～30 hours, more preferably 24～28 hours, most preferably is 24 hours.
(c) it is 40～50: 1 methylene dichloride and methanol solution that formula 11 compounds that reaction obtained adopt silica gel column chromatography to separate to obtain diastereomer, moving phase to be preferably volume ratio.
(d) the diastereomer isomer is reduced respectively, preferred reductive agent is tetrahydrochysene lithium aluminium, and reaction solvent is preferably tetrahydrofuran (THF).
The preparation method of the formula 7 among the preparation method of the present invention is:
Figure GPA00001137007000091
1. utilize initial compounds 1-p-methoxyphenyl-2-(3 ', 4 '-dimethoxy) phenyl-methyl acrylate (formula 1) through synthetic 3,6, the 7-trimethoxy of oxidative coupling reaction-9-phenanthrenecarboxylic acid methyl esters (formula 2);
Wherein: the oxygenant that carries out oxidative coupling reaction is preferably FERRIC CHLORIDE ANHYDROUS; The preferred dry methylene dichloride of reaction solvent, the mol ratio of FERRIC CHLORIDE ANHYDROUS and reactant 1-p-methoxyphenyl-2-(3 ', 4 '-dimethoxy) phenyl-methyl acrylate (formula 1) is 3～5: 1, preferred 3～4: 1, most preferably 3.5: 1; Preferred 0 ℃ of temperature of reaction is reacted and is slowly risen to room temperature after 2 hours; Stirring reaction is 3～6 hours under the room temperature condition, and preferred 3～5 hours, most preferably 3 hours; Slowly add saturated sodium bicarbonate aqueous solution then to there not being bubble to emerge, utilize silica gel column chromatography to separate behind the dry evaporate to dryness of organic layer, the moving phase preferred volume ratio is 3: 1 petroleum ether-ethyl acetate.
2. with 3,6,7-trimethoxy-9-phenanthrenecarboxylic acid methyl esters (formula 2) synthesizes (S)-(+)-3,6, the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-11, western pyridine diketone (formula 7) reference (J.Org.Chem.1983 in the 14-indoles, 48:4222.) the one-step optimization reaction conditions of going forward side by side, be through type 2 with L-L-glutamic acid diisopropyl ester through condensation, become acid amides, hydrolysis, Friedel-Crafts reaction to obtain.
The invention still further relates to a kind of pharmaceutical composition as the described compound of general formula I and pharmaceutically acceptable carrier that contains medicine effective dose.Described pharmaceutical composition can be tablet, capsule, pill, injection, sustained release preparation, controlled release preparation or particulate delivery system.
According to the present invention, the form that The compounds of this invention can isomer exists, and described " The compounds of this invention " comprises the isomer of this compound usually.
According to embodiment of the present invention, described The compounds of this invention also comprises hydrate, ester or the prodrug of acceptable salt, salt on its pharmacodynamics.
The invention still further relates to and contain as the The compounds of this invention of active ingredient and the pharmaceutical composition of conventional medicine vehicle or assistant agent.Usually pharmaceutical composition of the present invention contains the The compounds of this invention of 0.1～95 weight %.The general content of The compounds of this invention is 0.1～100mg in unit dosage form, and preferred unit dosage form contains 4～50mg.
The pharmaceutical composition of The compounds of this invention can be according to method preparation well known in the art.When being used for this purpose, if desired, The compounds of this invention and one or more solids or liquid medicine vehicle and/or assistant agent can be combined, make the suitable administration form or the dosage form that can be used as people's medicine or veterinary drug use.
The compounds of this invention or contain its pharmaceutical composition can the unit dosage form administration, route of administration can be enteron aisle or non-enteron aisle, as oral, muscle, subcutaneous, nasal cavity, oral mucosa, skin, peritonaeum or rectum etc.
The compounds of this invention or the route of administration that contains its pharmaceutical composition can be drug administration by injection.Injection comprises intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection and acupoint injection therapy etc.
Form of administration can be liquid dosage form, solid dosage.Can be true solution class, colloidal type, particulate formulations, emulsion dosage form, mixed suspension form as liquid dosage form.Other formulations are tablet, capsule, dripping pill, aerosol, pill, pulvis, solution, suspensoid, emulsion, granule, suppository, lyophilized injectable powder etc. for example.
The compounds of this invention can be made ordinary preparation, also can be sustained release preparation, controlled release preparation, targeting preparation and various particulate delivery system.
For example for the unit form of administration is made tablet, can be extensive use of various carrier well known in the art.Example about carrier is, for example thinner and absorption agent are as starch, dextrin, calcium sulfate, lactose, N.F,USP MANNITOL, sucrose, sodium-chlor, glucose, urea, calcium carbonate, white bole, Microcrystalline Cellulose, pure aluminium silicate etc.; Wetting agent and tackiness agent are as water, glycerine, polyoxyethylene glycol, ethanol, propyl alcohol, starch slurry, dextrin, syrup, honey, glucose solution, mucialga of arabic gummy, gelatine size, Xylo-Mucine, lac, methylcellulose gum, potassiumphosphate, polyvinylpyrrolidone etc.; Disintegrating agent, for example dry starch, alginates, agar powder, laminaran, sodium bicarbonate and Citric Acid, calcium carbonate, polyoxyethylene sorbitol fatty acid ester, sodium laurylsulfonate, methylcellulose gum, ethyl cellulose etc.; Disintegration inhibitor, for example sucrose, Tristearoylglycerol, theobroma oil, hydrogenation wet goods; Absorption enhancer, for example quaternary ammonium salt, sodium lauryl sulphate etc.; Lubricant, for example talcum powder, silicon-dioxide, W-Gum, stearate, boric acid, whiteruss, polyoxyethylene glycol etc.Tablet further can also be made coating tablet, for example sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablets and multilayer tablet.
For example for pill is made in the administration unit, can be extensive use of various carrier well known in the art.Example about carrier is, for example thinner and absorption agent are as glucose, lactose, starch, theobroma oil, hydrogenated vegetable oil, polyvinylpyrrolidone, single stearic acid glycerine lipoprotein, kaolin, talcum powder etc.; Tackiness agent is as gum arabic, tragacanth gum, gelatin, ethanol, honey, liquid sugar, rice paste or batter etc.; Disintegrating agent is as agar powder, dry starch, alginates, sodium laurylsulfonate, methylcellulose gum, ethyl cellulose etc.
For example for capsule is made in the administration unit, the effective constituent The compounds of this invention is mixed with above-mentioned various carriers, and the mixture that will obtain thus places hard gelatine capsule or soft capsule.Also the effective constituent The compounds of this invention can be made microcapsule, be suspended in and form suspensoid in the aqueous medium, in the hard capsule of also can packing into or make injection and use.
For example, The compounds of this invention is made injection preparation, as solution, suspensoid solution, emulsion, lyophilized injectable powder, this preparation can be moisture or non-water, can contain acceptable carrier, thinner, tackiness agent, lubricant, sanitas, tensio-active agent or dispersion agent on a kind of and/or multiple pharmacodynamics.Can be selected from water, ethanol, polyoxyethylene glycol, 1 as thinner, the isooctadecanol of ammediol, ethoxylation, the isooctadecanol of polyoxyization, polyoxyethylene sorbitol fat, fat acid esters etc.In addition, to ooze injection liquid in order preparing etc., can in injection preparation, to add proper amount of sodium chloride, glucose or glycerine, in addition, can also add conventional solubility promoter, buffer reagent, pH regulator agent etc.These auxiliary materials are that this area is commonly used.
In addition, as needs, also can in pharmaceutical preparation, add tinting material, sanitas, spices, correctives, sweeting agent or other material.
The invention discloses a kind of method for cancer that prevents and/or treats, comprise the The compounds of this invention that gives effective dose.Described cancer is selected from colorectal carcinoma, cancer of the stomach, ovarian cancer, cervical cancer, liver cancer, lung cancer, carcinoma of the pancreas.
The invention also discloses a kind of method that prevents and/or treats inflammatory disease, comprise give effective dose The compounds of this invention.
For reaching the medication purpose, strengthen result for the treatment of, medicine of the present invention or pharmaceutical composition can be with any known medication administrations.
The dosage of The compounds of this invention pharmaceutical composition depends on many factors, for example to prevent or treat character and the severity of disease, the sex of patient or animal, age, body weight, personality and individual reaction, route of administration, administration number of times, therapeutic purpose, therefore therapeutic dose of the present invention can have large-scale variation.In general, the using dosage of Chinese materia medica composition of the present invention is well known to a person skilled in the art.Can be according to the actual drug quantity that contains in the preparation last in the The compounds of this invention composition, in addition suitable adjustment to reach the requirement of its treatment significant quantity, is finished prevention of the present invention or therapeutic purpose.The suitable dose scope of the every day of The compounds of this invention: the consumption of compound of the present invention is 0.001～100mg/Kg body weight, is preferably 0.1～60mg/Kg body weight, and more preferably 1～30mg/Kg body weight most preferably is 2～15mg/Kg body weight.Be 10～500mg The compounds of this invention every day that adult patient is taken, and is preferably 20～100mg, can once take or divide and take for 2～3 times; The dosage of children taking is preferably 10～20mg/kg body weight according to every kg body weight 5～30mg.Above-mentioned dosage can the single dose form or be divided into several, for example two, three or four dosage form administrations, this is subject to administration doctor's clinical experience and the dosage regimen for the treatment of means.Compound of the present invention or composition can be taken separately, or merge use with other treatment medicine or symptomatic drugs.
The invention still further relates to the application, particularly application in cancers such as colorectal carcinoma, cancer of the stomach, ovarian cancer, cervical cancer, liver cancer, lung cancer and carcinoma of the pancreas of compound of the present invention in the medicine of preparation treatment cancer and/or inflammatory disease.
Embodiment
Used initial compounds in the embodiment of the invention, can be according to the ordinary method of this area and/or method well known to those skilled in the art preparation, and can be by the preparation of following preparation example for example.
The following examples are used for further specifying the present invention, but this and do not mean that any limitation of the invention.
The english abbreviation explanation:
DCM: methylene dichloride
DMF: dimethyl formamide
DMSO: dimethyl sulfoxide (DMSO)
ESI: electron spray ionisation
THF: tetrahydrofuran (THF)
TMS: tetramethylsilane
LAH: Lithium Aluminium Hydride
Embodiment 1:(13aS, 14R)-14-methoxyl group-3,6, western pyridine (B-2) and (13aS, 14S)-14-methoxyl group-3,6, western pyridine (B-1) synthesizes in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles
(1) 3, the preparation of 6,7-trimethoxy-9-phenanthrenecarboxylic acid methyl esters (2):
Figure GPA00001137007000121
In the reaction flask of super-dry, add methylene dichloride 200mL to 500mL, with 10.17g reactant 1-p-methoxyphenyl-2-(3 ', 4 '-dimethoxy) phenyl-methyl acrylate is dissolved in wherein, it is 0 ℃ that ice bath keeps temperature of reaction, stir and add FERRIC CHLORIDE ANHYDROUS 16.9g down, vigorous stirring reaction kept 2 hours at 0 ℃, reacted 3 hours after slowly rising to room temperature again, in reaction solution, slowly add saturated sodium bicarbonate aqueous solution then, there is not bubble to emerge to reaction solution, with the mixed solution layering, the organic layer drying, evaporate to dryness, silica gel column chromatography, moving phase is petroleum ether-ethyl acetate (3: 1), obtains product 6.7g, yield 66%.
Nucleus magnetic hydrogen spectrum (300MHz, [D 6] DMSO, 25 ℃, mark in the TMS): 8.43 (1H, s), 8.42 (1H, s), 8.12 (1H, s), 8.08 (1H, J=2.0Hz), 8.02 (1H, J=9.0), 7.27 (1H, dd, J=2.0,9.0Hz), 4.04 (3H, s, MeO), 4.02 (3H, s, MeO), 3.93 (3H, s, MeO), 3.90 (3H, s, MeO).
(2) (13aS, 14S)-14-methoxyl group-3,6, in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-11-indoles western pyridine ketone (B-3) and (13aS, 14R)-14-methoxyl group-3,6, western pyridine ketone (B-4) in luxuriant and rich with fragrance parallel [9, the 10-b]-11-indoles of 7-trimethoxy-9-:
Figure GPA00001137007000131
With reactant (S)-N-3, the luxuriant and rich with fragrance a pair of horses going side by side [9 of 6,7-trimethoxy-9-, 10-b]-11, western pyridine diketone (7) in the 14-indoles (J.Org.Chem.1983,48:4222.) 0.2g is dissolved in the 5mL methylene dichloride, add 5mL methyl alcohol again, slowly add sodium borohydride 0.1g, stirring reaction 30min under the room temperature adds saturated ammonium chloride solution 10mL then in reaction solution, stir layering, organic layer drying, evaporate to dryness, it is not purified to obtain product, directly carries out next step reaction.
Above product is dissolved in the methylene dichloride of 5mL drying, adds 70% NaH 0.07g under the protection of inert gas, at room temperature stirring reaction 30min drips CH 3I 0.16mL, stirring reaction 24h under the room temperature adds saturated NH then then 4Cl solution 10mL termination reaction, the organic layer washing, drying is carried out silica gel column chromatography and is separated behind the evaporate to dryness, moving phase is methylene chloride-methanol (50: 1), obtain two diastereomer intermediates respectively, be respectively (13aS, 14R)-14-methoxyl group-3,6, western pyridine ketone (B-4) in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-11-indoles is 60mg, yield 29%, (13aS, 14S)-14-methoxyl group-3,6, the luxuriant and rich with fragrance a pair of horses going side by side [9 of 7-trimethoxy-9-, 10-b]-the 11-indoles in western pyridine ketone (B-3), be 80mg, yield 38%.Nucleus magnetic hydrogen spectrum (500MHz, the CDCl of intermediate (B-4) 3, 25 ℃, mark in the TMS): 8.21 (1H, d, J=9.0Hz), 7.22 (1H, dd, J=9.0Hz, 2Hz), 7.88 (1H, d, J=2Hz), 7.91 (1H, s), 7.21 (1H, s), 5.38 (1H, d, J=17Hz), 4.43 (1H, d, J=17Hz), 5.15 (1H, d, J=7Hz), 4.07 (1H, m), 4.12 (3H, s, MeO), 4.06 (3H, s, MeO), 4.02 (3H, s, MeO), 3.19 (3H, s, MeO), and 2.71-2.61 (1H, m), 2.60-2.57 (2H, m), 2.28-2.21 (1H, m).Nucleus magnetic hydrogen spectrum (500MHz, the CDCl of intermediate (B-3) 3, 25 ℃, mark in the TMS): 8.19 (1H, d, J=9.5Hz), 7.27 (1H, dd, J=9.0Hz, 2Hz), 7.92 (1H, d, J=2Hz), 7.93 (1H, s), 7.26 (1H, s), 5.36 (1H, d, J=17.5Hz), 4.63 (1H, d, J=17.5Hz), 5.19 (1H, m), 3.96 (1H, m), 4.12 (3H, s, MeO), 4.06 (3H, s, MeO), 4.02 (3H, s, MeO), 3.16 (3H, s, MeO), and 2.71-2.65 (1H, m), 2.60-2.51 (2H, m), 2.34-2.30 (1H, m).
(3) (13aS, 14R)-14-methoxyl group-3,6, western pyridine (B-2) in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles
Figure GPA00001137007000141
The above 60mg intermediate (B-4) that obtains is dissolved in the tetrahydrofuran (THF) of 5mL; add tetrahydrochysene lithium aluminium 40mg under the protection of inert gas; shading back flow reaction 2h; then reaction solution is cooled to room temperature; slowly drip the mixed solution of tetrahydrofuran (THF)/water (1: 1) to there not being bubble to overflow; add methylene dichloride 5mL then in mixed solution, mixed solution is filtered, filter residue is washed with methylene dichloride; the merging filtrate evaporate to dryness; obtain product (13aS, 14R)-14-methoxyl group-3,6; the luxuriant and rich with fragrance a pair of horses going side by side [9 of 7-trimethoxy-9-; 10-b]-indoles in western pyridine 40mg, nucleus magnetic hydrogen spectrum (500MHz, CDCl 3, 25 ℃, mark in the TMS): 8.18 (1H, d, J=9.0Hz), 7.22 (1H, dd, J=9.0Hz, 2Hz), 7.87 (1H, d, J=2Hz), 7.91 (1H, s), 7.16 (1H, s), 5.14 (1H, d, J=7.2Hz), 4.51 (1H, d, J=14.4Hz), 3.80 (1H, d, J=14.4Hz), 4.10 (3H, s, MeO), 4.05 (3H, s, MeO), 4.01 (3H, s, MeO), 3.24 (3H, s, MeO), 3.36 (1H, m), 2.77 (1H, m), 2.60 (1H, m), 2.44 (1H, m), 1.95 (3H, m).HRMS(ESI)calcd?for[M+H] +C 24H 28NO 4394.2012，found?394.2024。
(4) (13aS, 14S)-14-methoxyl group-3,6, western pyridine (B-1) in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles
Figure GPA00001137007000142
The above 80mg intermediate (B-3) that obtains is dissolved in the tetrahydrofuran (THF) of 5mL; add tetrahydrochysene lithium aluminium 50mg under the protection of inert gas; shading back flow reaction 2h; then reaction solution is cooled to room temperature; slowly drip the mixed solution of tetrahydrofuran (THF)/water (1: 1) to there not being bubble to overflow; add methylene dichloride 5mL then in mixed solution, mixed solution is filtered, filter residue is washed with methylene dichloride; the merging filtrate evaporate to dryness; obtain product (13aS, 14S)-14-methoxyl group-3,6; the luxuriant and rich with fragrance a pair of horses going side by side [9 of 7-trimethoxy-9-; 10-b]-indoles in western pyridine 60mg, nucleus magnetic hydrogen spectrum (500MHz, CDCl 3, 25 ℃, mark in the TMS): 8.26 (1H, d, J=8.8Hz), 7.24 (1H, dd, J=8.8Hz, 2Hz), 7.90 (1H, d, J=2Hz), 7.93 (1H, s), 7.25 (1H, s), 5.11 (1H, s), 4.66 (1H, d, J=15Hz), 3.52 (1H, d, J=15Hz), 4.11 (3H, s, MeO), 4.065 (3H, s, MeO), 4.02 (3H, s, MeO), 3.37 (3H, s, MeO), 3.44 (1H, m), 2.55 (1H, m), 2.33 (2H, m), 2.02 (2H, m), 1.93 (1H, m).HRMS(ESI)calcd?for[M+H] +C 24H 28NO 4394.2012，found?394.2023。
Embodiment 2:(13aS, 14R)-14-Propylamino-3,6, western pyridine (D-2) and (13aS, 14S)-14-Propylamino-3,6, western pyridine (D-1) synthesizes in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles
(1) (13aS, 14S)-14-Propylamino-3,6, in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-11-indoles western pyridine ketone (D-3) and (13aS, 14R)-14-Propylamino-3,6, western pyridine ketone (D-4) in luxuriant and rich with fragrance parallel [9, the 10-b]-11-indoles of 7-trimethoxy-9-
Under-20 ℃ with reactant (S)-(+)-N-3; 6; the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-11, western pyridine diketone (7) 0.2g is dissolved in the 2mL methylene dichloride in the 14-indoles; add propylamine 0.1mL under the protection of inert gas; titanium tetrachloride 0.028mL; stirring reaction 1h under this temperature rises to room temperature and reacts 24h more then, adds sherwood oil 1.5mL in reaction solution; methylene dichloride 2mL; stirred 5 minutes; filter with diatomite then, the filtrate evaporate to dryness is with a spot of methylene chloride mixed solution dissolving; adding sodium borohydride 0.1g reduces; behind the reaction 30min, in reaction solution, add saturated ammonium chloride solution 10mL termination reaction, the organic layer washing; dry; evaporate to dryness; separate with silica gel column chromatography then; moving phase is methylene chloride (40: 1), successively obtains two intermediates, is respectively intermediate 1 (13aS; 14S)-14-Propylamino-3; western pyridine ketone (D-3) in the luxuriant and rich with fragrance a pair of horses going side by side of 6,7-trimethoxy-9-[9,10-b]-11-indoles; be 86mg, yield 39%.Intermediate 2 (13aS, 14R)-14-Propylamino-3,6, western pyridine ketone (D-4) in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-11-indoles is 120mg, yield 54%.Nucleus magnetic hydrogen spectrum (500MHz, the CDCl of intermediate 1 (D-3) 3, 25 ℃, mark in the TMS): 8.08 (1H, d, J=9.5Hz), 7.27 (1H, dd, J=9.5Hz, 2Hz), 7.93 (1H, d, J=2Hz), 7.92 (1H, s), 7.21 (1H, s), 5.32 (1H, d, J=17.5Hz), 4.59 (1H, d, J=17.5Hz), 4.40 (1H, s), 3.94 (1H, m), 4.11 (3H, s, MeO), 4.05 (3H, s, MeO), 4.03 (3H, s, MeO), 2.84-2.73 (2H, m), 2.68-2.64 (1H, m), 2.58-2.44 (2H, m), 2.29-2.22 (1H, m), 1.35 (2H, m), 0.82 (3H, t).Nucleus magnetic hydrogen spectrum (500MHz, the CDCl of intermediate 2 (D-4) 3, 25 ℃, mark in the TMS): 7.98 (1H, d, J=8.5Hz), 7.22 (1H, dd, J=8.5Hz, 2Hz), 7.88 (1H, d, J=2Hz), 7.89 (1H, s), 7.23 (1H, s), 5.41 (1H, d, J=16.5Hz), 4.35 (1H, d, J=16.5Hz), 4.41 (1H, d, J=6Hz), 4.00 (1H, m), 4.11 (3H, s, MeO), 4.06 (3H, s, MeO), 4.02 (3H, s, MeO), and 2.73-2.63 (2H, m), 2.60-2.50 (3H, m), 2.17-2,09 (1H, m), 1.42 (2H, m), 0.85 (3H, t).
(2) (13aS, 14S)-14-Propylamino-3,6, western pyridine (D-1) in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles
(D-1)
The above 86mg intermediate 1 (D-3) that obtains is dissolved in the tetrahydrofuran (THF) of 5mL, adds tetrahydrochysene lithium aluminium 50mg under the protection of inert gas, shading back flow reaction 2h; then reaction solution is cooled to room temperature; slowly drip the mixed solution of tetrahydrofuran (THF)/water (volume ratio 1: 1) to there not being bubble to overflow, in mixed solution, add methylene dichloride 5mL then, mixed solution is filtered; filter residue is washed with methylene dichloride; the merging filtrate evaporate to dryness, product is oily, drips dilute hydrochloric acid to product in this product and dissolves; filter; filtrate is transferred pH to 8 with 10% NaOH solution, and product is solid-state separates out, and product is leached; a small amount of washing; place moisture eliminator vacuum-drying under the room temperature, obtain product (13aS, 14S)-14-Propylamino-3; 6; western pyridine (D-1) 49mg in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles, 58%; nucleus magnetic hydrogen spectrum (500MHz, CDCl 3, 25 ℃, mark in the TMS): 8.04 (1H, d, J=9.0Hz), 7.27 (1H, dd, J=9.0Hz, 2Hz), 7.92 (1H, d, J=2Hz), 7.91 (1H, s), 7.18 (1H, s), 4.67 (1H, d, J=15Hz), 3.68 (1H, d, J=15Hz), 4.24 (1H, m), 4.10 (3H, s, MeO), 4.05 (3H, s, MeO), 4.02 (3H, s, MeO), 3.58-3.51 (1H, m), 2.98 (1H, m), 2.89 (1H, m), 2.56 (1H, m), 2.44 (1H, m), 2.21 (1H, m), 2.02-1.89 (3H, m), 1.43 (2H, m), 0.88 (3H, t).HRMS(ESI)calcd?for[M] +C 26H 32N 2O 3420.2412，found?420.2411。
(3) (13aS, 14R)-14-Propylamino-3,6, western pyridine (D-2) in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles
Figure GPA00001137007000161
The above 120mg intermediate 2 (D-4) that obtains is dissolved in the tetrahydrofuran (THF) of 8mL, adds tetrahydrochysene lithium aluminium 60mg under the protection of inert gas, shading back flow reaction 2h; then reaction solution is cooled to room temperature; slowly drip the mixed solution of tetrahydrofuran (THF)/water (volume ratio 1: 1) to there not being bubble to overflow, in mixed solution, add methylene dichloride 8mL then, mixed solution is filtered; filter residue is washed with methylene dichloride; the merging filtrate evaporate to dryness, product is oily, drips dilute hydrochloric acid to product in this product and dissolves; filter; filtrate is transferred pH to 8 with 10% NaOH solution, and product is solid-state separates out, and product is leached; a small amount of washing; place moisture eliminator vacuum-drying under the room temperature, obtain product (13aS, 14R)-14-Propylamino-3; 6; western pyridine (D-2) 75mg in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles, yield 64.6%; nucleus magnetic hydrogen spectrum (500MHz, CDCl 3, 25 ℃, mark in the TMS): 8.07 (1H, d, J=9.0Hz), 7.23 (1H, dd, J=9.0Hz, 2Hz), 7.90 (1H, d, J=2Hz), 7.91 (1H, s), 7.19 (1H, s), 4.56 (1H, m), 4.52 (1H, d, J=15Hz), 3.69 (1H, d, J=15Hz), 4.11 (3H, s, MeO), 4.05 (3H, s, MeO), 4.02 (3H, s, MeO), 3.25 (1H, m), 3.00 (2H, m), 2.65 (1H, m), 2.56 (1H, m), 2.36 (1H, m), 2.02-1.87 (3H, m), 1.42 (2H, m), 0.83 (3H, t).HRMS(ESI)calcd?for[M] +C 26H 32N 2O 3420.2412，found?420.2392。
Embodiment 3:(13aS, 14R)-14-isopropylamine base-3,6, western pyridine (E-2) and (13aS, 14S)-14-isopropylamine base-3,6, western pyridine (E-1) synthesizes in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles
(1) (13aS, 14S)-14-isopropylamine base-3,6, in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-11-indoles western pyridine ketone (E-3) and (13aS, 14R)-14-isopropylamine base-3,6, western pyridine ketone (E-4) in luxuriant and rich with fragrance parallel [9, the 10-b]-11-indoles of 7-trimethoxy-9-
Figure GPA00001137007000171
Under-20 ℃ with reactant (S)-(+)-N-3; 6; the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-11, western pyridine diketone (7) 0.2g is dissolved in the 2mL methylene dichloride in the 14-indoles; add Isopropylamine 0.1mL under the protection of inert gas; titanium tetrachloride 0.028mL; stirring reaction 1h under this temperature rises to room temperature and reacts 24h more then, adds sherwood oil 1.5mL in reaction solution; methylene dichloride 2mL; stirred 5 minutes; filter with diatomite then, the filtrate evaporate to dryness is with a spot of methylene chloride mixed solution dissolving; adding sodium borohydride 0.1g reduces; behind the reaction 30min, in reaction solution, add saturated ammonium chloride solution 10mL termination reaction, the organic layer washing; dry; evaporate to dryness; separate with silica gel column chromatography then; moving phase is methylene chloride (volume ratio 50: 1), successively obtains two intermediates, is respectively intermediate 1 (13aS; 14S)-14-isopropylamine base-3; western pyridine ketone (E-3) in the luxuriant and rich with fragrance a pair of horses going side by side of 6,7-trimethoxy-9-[9,10-b]-11-indoles; be 50mg, yield 22.5%.Intermediate 2 (13aS, 14R)-14-isopropylamine base-3,6, western pyridine ketone (E-4) in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-11-indoles is 110mg, yield 49.5%.Nucleus magnetic hydrogen spectrum (500MHz, the CDCl of intermediate 1 (E-3) 3, 25 ℃, mark in the TMS): 8.11 (1H, d, J=8.5Hz), 7.26 (1H, dd, J=8.5Hz, 2Hz), 7.93 (1H, d, J=2Hz), 7.92 (1H, s), 7.21 (1H, s), 5.31 (1H, d, J=18Hz), 4.65 (1H, d, J=18Hz), 4.46 (1H, s), 3.96 (1H, m), 4.12 (3H, s, MeO), 4.05 (3H, s, MeO), 4.03 (3H, s, MeO), 3.03 (1H, m), 2.76 (1H, m), 2.53-2.51 (2H, m), 2.24 (1H, m), 1.16 (3H, m), 0.84 (3H, m).Nucleus magnetic hydrogen spectrum (500MHz, the CDCl of intermediate 2 (E-4) 3, 25 ℃, mark in the TMS): 8.06 (1H, d, J=8.5Hz), 7.25 (1H, dd, J=8.5Hz, 2Hz), 7.88 (1H, d, J=2Hz), 7.89 (1H, s), 7.22 (1H, s), 5.48 (1H, d, J=16.5Hz), 4.34 (1H, d, J=16.5Hz), 4.63 (1H, d, J=6Hz), 4.02 (1H, m), 4.11 (3H, s, MeO), 4.07 (3H, s, MeO), 4.02 (3H, s, MeO), 3.07 (1H, m), 2.70 (1H, m), 2.53 (2H, m), 2.10 (1H, m), 1.30 (3H, d, J=5.5Hz), 1.02 (3H, d, J=5.5Hz).
(2) (13aS, 14S)-14-isopropylamine base-3,6, western pyridine (E-1) in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles
Figure GPA00001137007000181
The above 50mg intermediate 1 (E-3) that obtains is dissolved in the tetrahydrofuran (THF) of 5mL, adds tetrahydrochysene lithium aluminium 50mg under the protection of inert gas, shading back flow reaction 2h; then reaction solution is cooled to room temperature; slowly drip the mixed solution of tetrahydrofuran (THF)/water (1: 1) to there not being bubble to overflow, in mixed solution, add methylene dichloride 5mL then, mixed solution is filtered; filter residue is washed with methylene dichloride; the merging filtrate evaporate to dryness, product is oily, drips dilute hydrochloric acid to product in this product and dissolves; filter; filtrate is transferred pH to 8 with 10% NaOH solution, and product is solid-state separates out, and product is leached; a small amount of washing; place moisture eliminator vacuum-drying under the room temperature, obtain product (13aS, 14S)-14-isopropylamine base-3; 6; western pyridine (E-1) 45mg in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles, 93%; nucleus magnetic hydrogen spectrum (500MHz, CDCl 3, 25 ℃, mark in the TMS): 8.24 (1H, d, J=9.0Hz), 7.23 (1H, dd, J=9.0Hz, 2Hz), 7.91 (1H, d, J=2Hz), 7.92 (1H, s), 7.18 (1H, s), 4.69 (1H, d, J=14.5Hz), 3.61 (1H, d, J=14.5Hz), 4.45 (1H, m), 4.11 (3H, s, MeO), 4.05 (3H, s, MeO), 4.02 (3H, s, MeO), 3.50 (1H, m), 3.24 (1H, m), 2.61 (1H, m), 2.42 (1H, m), 2.29 (1H, m), 1.98 (1H, m), 1.89 (2H, m), 1.25 (3H, m), 1.02 (3H, m).HRMS(ESI)calcd?for[M] +C 26H 32N 2O 3421.2359，found?421.2367。
(3) (13aS, 14R)-14-isopropylamine base-3,6, western pyridine (E-2) in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles
Figure GPA00001137007000182
The above 110mg intermediate 2 (E-4) that obtains is dissolved in the tetrahydrofuran (THF) of 8mL, adds tetrahydrochysene lithium aluminium 60mg under the protection of inert gas, shading back flow reaction 2h; then reaction solution is cooled to room temperature; slowly drip the mixed solution of tetrahydrofuran (THF)/water (volume ratio 1: 1) to there not being bubble to overflow, in mixed solution, add methylene dichloride 8mL then, mixed solution is filtered; filter residue is washed with methylene dichloride; the merging filtrate evaporate to dryness, product is oily, drips dilute hydrochloric acid to product in this product and dissolves; filter; filtrate is transferred pH to 8 with 10% NaOH solution, and product is solid-state separates out, and product is leached; a small amount of washing; place moisture eliminator vacuum-drying under the room temperature, obtain product (13aS, 14R)-14-isopropylamine base-3; 6; western pyridine (E-2) 75mg in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles, yield 70.5%; nucleus magnetic hydrogen spectrum (500MHz, CDCl 3, 25 ℃, mark in the TMS): 8.18 (1H, d, J=9.0Hz), 7.19 (1H, dd, J=9.0Hz, 2Hz), 7.86 (1H, d, J=2Hz), 7.91 (1H, s), 7.15 (1H, s), 4.63 (1H, m), 4.42 (1H, d, J=14Hz), 3.72 (1H, d, J=14Hz), 4.10 (3H, s, MeO), 4.05 (3H, s, MeO), 4.01 (3H, s, MeO), 3.28 (1H, m), 3.11 (1H, m), 2.53 (2H, m), 2.43 (1H, m), 1.93 (3H, m), 1.28 (3H, m), 0.87 (3H, m).HRMS(ESI)calcd?for[M+H] +C 26H 33N 2O 3421.2485，found?421.2495。
Embodiment 4:(13aS, 14R)-14-cyclopentamine base-3,6, western pyridine (F-2) and (13aS, 14S)-14-cyclopentamine base-3,6, western pyridine (F-1) synthesizes in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles
(1) (13aS, 14S)-14-cyclopentamine base-3,6, in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-11-indoles western pyridine ketone (F-3) and (13aS, 14R)-14-cyclopentamine base-3,6, western pyridine ketone (F-4) in luxuriant and rich with fragrance parallel [9, the 10-b]-11-indoles of 7-trimethoxy-9-
Under-20 ℃ with reactant (S)-(+)-N-3; 6; the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-11, western pyridine diketone (7) 0.2g is dissolved in the 2mL methylene dichloride in the 14-indoles; add cyclopentamine 0.1mL under the protection of inert gas; titanium tetrachloride 0.028mL; stirring reaction 1h under this temperature rises to room temperature and reacts 24h more then, adds sherwood oil 1.5mL in reaction solution; methylene dichloride 2mL; stirred 5 minutes; filter with diatomite then, the filtrate evaporate to dryness is with a spot of methylene chloride mixed solution dissolving; adding sodium borohydride 0.1g reduces; behind the reaction 30min, in reaction solution, add saturated ammonium chloride solution 10mL termination reaction, the organic layer washing; dry; evaporate to dryness; separate with silica gel column chromatography then; moving phase is methylene chloride (volume ratio 50: 1), successively obtains two intermediates, is respectively intermediate 1 (13aS; 14S)-14-cyclopentamine base-3; western pyridine ketone (F-3) in the luxuriant and rich with fragrance a pair of horses going side by side of 6,7-trimethoxy-9-[9,10-b]-11-indoles; be 62mg, yield 26.3%.Intermediate 2 (13aS, 14R)-14-cyclopentamine base-3,6, western pyridine ketone (F-4) in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-11-indoles is 132mg, yield 56.1%.Nucleus magnetic hydrogen spectrum (500MHz, the CDCl of intermediate 1 (F-3) 3, 25 ℃, mark in the TMS): 8.15 (1H, d, J=8.5Hz), 7.26 (1H, dd, J=8.5Hz, 2Hz), 7.92 (1H, d, J=2Hz), 7.93 (1H, s), 7.21 (1H, s), 5.30 (1H, d, J=17.5Hz), 4.65 (1H, d, J=17.5Hz), 4.43 (1H, s), 3.97 (1H, m), 4.12 (3H, s, MeO), 4.05 (3H, s, MeO), 4.04 (3H, s, MeO), 3.22 (1H, m), 2.72 (1H, m), 2.56-2.51 (2H, m), 2.25 (1H, m), 1.79 (1H, m), 1.72-1.25 (7H, m), 1.05 (1H, m).Nucleus magnetic hydrogen spectrum (500MHz, the CDCl of intermediate 2 (F-4) 3, 25 ℃, mark in the TMS): 8.05 (1H, d, J=9Hz), 7.21 (1H, dd, J=9Hz, 2Hz), 7.88 (1H, d, J=2Hz), 7.89 (1H, s), 7.23 (1H, s), 5.44 (1H, d, J=16.5Hz), 4.33 (1H, d, J=16.5Hz), 4.54 (1H, d, J=4.5Hz), 4.02 (1H, m), 4.10 (3H, s, MeO), 4.06 (3H, s, MeO), 4.02 (3H, s, MeO), 3.25 (1H, m), 2.70 (1H, m), 2.55 (2H, m), 2.13 (1H, m), 1.95 (1H, m), 1.77-1.25 (7H, m), 1.15 (1H, m).
(2) (13aS, 14S)-14-cyclopentamine base-3,6, western pyridine (F-1) in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles
Figure GPA00001137007000201
The above 62mg intermediate 1 (F-3) that obtains is dissolved in the tetrahydrofuran (THF) of 5mL, adds tetrahydrochysene lithium aluminium 50mg under the protection of inert gas, shading back flow reaction 2h; then reaction solution is cooled to room temperature; slowly drip the mixed solution of tetrahydrofuran (THF)/water (volume ratio 1: 1) to there not being bubble to overflow, in mixed solution, add methylene dichloride 5mL then, mixed solution is filtered; filter residue is washed with methylene dichloride; the merging filtrate evaporate to dryness, product is oily, drips dilute hydrochloric acid to product in this product and dissolves; filter; filtrate is transferred pH to 8 with 10% NaOH solution, and product is solid-state separates out, and product is leached; a small amount of washing; place moisture eliminator vacuum-drying under the room temperature, obtain product (13aS, 14S)-14-cyclopentamine base-3; 6; western pyridine (F-1) 47mg in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles, 78.2%; nucleus magnetic hydrogen spectrum (500MHz, CDCl 3, 25 ℃, mark in the TMS): 8.24 (1H, d, J=8.5Hz), 7.23 (1H, dd, J=8.5Hz, 2Hz), 7.90 (1H, d, J=2Hz), 7.92 (1H, s), 7.18 (1H, s), 4.67 (1H, d, J=15Hz), 3.60 (1H, d, J=15Hz), 4.39 (1H, m), 4.10 (3H, s, MeO), 4.05 (3H, s, MeO), 4.02 (3H, s, MeO), 3.48 (1H, m), 3.36 (1H, m), 2.61 (1H, m), 2.42 (1H, m), 2.30 (1H, m), 1.98 (1H, m), 1.89 (2H, m), 1.83-1.08 (8H, m).HRMS(ESI)calcd?for[M+H] +C 28H 35N 2O 3447.2642，found?447.2653。
(3) (13aS, 14R)-14-cyclopentamine base-3,6, western pyridine (F-2) in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles
The above 132mg intermediate 2 (F-4) that obtains is dissolved in the tetrahydrofuran (THF) of 8mL, adds tetrahydrochysene lithium aluminium 60mg under the protection of inert gas, shading back flow reaction 2h; then reaction solution is cooled to room temperature; slowly drip the mixed solution of tetrahydrofuran (THF)/water (volume ratio 1: 1) to there not being bubble to overflow, in mixed solution, add methylene dichloride 8mL then, mixed solution is filtered; filter residue is washed with methylene dichloride; the merging filtrate evaporate to dryness, product is oily, drips dilute hydrochloric acid to product in this product and dissolves; filter; filtrate is transferred pH to 8 with 10% NaOH solution, and product is solid-state separates out, and product is leached; a small amount of washing; place moisture eliminator vacuum-drying under the room temperature, obtain product (13aS, 14R)-14-cyclopentamine base-3; 6; western pyridine (F-2) 95mg in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles, yield 74.2%; nucleus magnetic hydrogen spectrum (500MHz, CDCl 3, 25 ℃, mark in the TMS): 8.16 (1H, d, J=8.5Hz), 7.18 (1H, dd, J=8.5Hz, 2Hz), 7.86 (1H, d, J=2Hz), 7.89 (1H, s), 7.15 (1H, s), 4.56 (1H, m), 4.44 (1H, d, J=14Hz), 3.72 (1H, d, J=14Hz), 4.10 (3H, s, MeO), 4.05 (3H, s, MeO), 4.01 (3H, s, MeO), 3.29 (2H, m), 2.53 (2H, m), 2.60-2.42 (3H, m), 1.93 (3H, m), 1.74-1.12 (8H, m).HRMS(ESI)calcd?for[M+H] +C 28H 35N 2O 3447.2642，found?447.2650。
Embodiment 5:(13aS, 14R)-14-cyclohexylamino-3,6, western pyridine (G-2) and (13aS, 14S)-14-cyclohexylamino-3,6, western pyridine (G-1) synthesizes in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles
(1) (13aS, 14S)-14-cyclohexylamino-3,6, in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-11-indoles western pyridine ketone (G-3) and (13aS, 14R)-14-cyclohexylamino-3,6, western pyridine ketone (G-4) in luxuriant and rich with fragrance parallel [9, the 10-b]-11-indoles of 7-trimethoxy-9-
Figure GPA00001137007000211
Under-20 ℃ with reactant (S)-(+)-N-3; 6; the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-11, western pyridine diketone (7) 0.2g is dissolved in the 2mL methylene dichloride in the 14-indoles; add hexahydroaniline 0.1mL under the protection of inert gas; titanium tetrachloride 0.028mL; stirring reaction 1h under this temperature rises to room temperature and reacts 24h more then, adds sherwood oil 1.5mL in reaction solution; methylene dichloride 2mL; stirred 5 minutes; filter with diatomite then, the filtrate evaporate to dryness is with a spot of methylene chloride mixed solution dissolving; adding sodium borohydride 0.1g reduces; behind the reaction 30min, in reaction solution, add saturated ammonium chloride solution 10mL termination reaction, the organic layer washing; dry; evaporate to dryness; separate with silica gel column chromatography then; moving phase is methylene chloride (volume ratio 50: 1), successively obtains two intermediates, is respectively intermediate 1 (13aS; 14S)-14-cyclohexylamino-3; western pyridine ketone (G-3) in the luxuriant and rich with fragrance a pair of horses going side by side of 6,7-trimethoxy-9-[9,10-b]-11-indoles; be 65mg, yield 26.8%.Intermediate 2 (13aS, 14R)-14-cyclohexylamino-3,6, western pyridine ketone (G-4) in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-11-indoles is 125mg, yield 51.5%.Nucleus magnetic hydrogen spectrum (500MHz, the CDCl of intermediate 1 (G-3) 3, 25 ℃, mark in the TMS): 8.09 (1H, d, J=9Hz), 7.24 (1H, dd, J=9Hz, 2Hz), 7.93 (1H, d, J=2Hz), 7.93 (1H, s), 7.21 (1H, s), 5.31 (1H, d, J=17.5Hz), 4.64 (1H, d, J=17.5Hz), 4.51 (1H, s), 3.97 (1H, m), 4.12 (3H, s, MeO), 4.06 (3H, s, MeO), 4.04 (3H, s, MeO), 3.22 (1H, m), 2.75 (1H, m), 2.63 (1H, m), 2.50 (2H, m), 2.24 (1H, m), 2.12 (1H, m), 1.77 (1H, m), 1.59 (3H, m), 1.27-0.98 (5H, m).Nucleus magnetic hydrogen spectrum (500MHz, the CDCl of intermediate 2 (G-4) 3, 25 ℃, mark in the TMS): 8.08 (1H, d, J=9Hz), 7.22 (1H, dd, J=9Hz, 2.5Hz), 7.88 (1H, d, J=2.5Hz), 7.88 (1H, s), 7.24 (1H, s), 5.46 (1H, d, J=16Hz), 4.33 (1H, d, J=16Hz), 4.69 (1H, d, J=3.5Hz), 4.02 (1H, m), 4.10 (3H, s, MeO), 4.06 (3H, s, MeO), 4.02 (3H, s, MeO), 2.71 (2H, m), 2.53 (2H, m), 2.33 (1H, m), 2.10 (1H, m), 1.83 (1H, m), 1.63 (3H, m), 1.32-1.01 (5H, m).
(2) (13aS, 14S)-14-cyclohexylamino-3,6, western pyridine (G-1) in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles
Figure GPA00001137007000221
The above 65mg intermediate 1 (G-3) that obtains is dissolved in the tetrahydrofuran (THF) of 5mL, adds tetrahydrochysene lithium aluminium 50mg under the protection of inert gas, shading back flow reaction 2h; then reaction solution is cooled to room temperature; slowly drip the mixed solution of tetrahydrofuran (THF)/water (volume ratio 1: 1) to there not being bubble to overflow, in mixed solution, add methylene dichloride 5mL then, mixed solution is filtered; filter residue is washed with methylene dichloride; the merging filtrate evaporate to dryness, product is oily, drips dilute hydrochloric acid to product in this product and dissolves; filter; filtrate is transferred pH to 8 with 10% NaOH solution, and product is solid-state separates out, and product is leached; a small amount of washing; place moisture eliminator vacuum-drying under the room temperature, obtain product (13aS, 14S)-14-cyclohexylamino-3; 6; western pyridine (G-1) 52mg in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles, 82.4%; nucleus magnetic hydrogen spectrum (500MHz, CDCl 3, 25 ℃, mark in the TMS): 8.23 (1H, d, J=9.5Hz), 7.23 (1H, dd, J=9.5Hz, 2Hz), 7.90 (1H, d, J=2Hz), 7.91 (1H, s), 7.17 (1H, s), 4.68 (1H, d, J=15Hz), 3.62 (1H, d, J=15Hz), 4.48 (1H, m), 4.10 (3H, s, MeO), 4.05 (3H, s, MeO), 4.02 (3H, s, MeO), 3.50 (1H, m), 2.80 (1H, m), 2.62 (1H, m), 2.44 (1H, m), 1.99-1.90 (4H, m), 1.73-1.54 (4H, m), 1.14 (5H, m).HRMS(ESI)calcd?for[M] +C 29H 36N 2O 3460.2725，found?460.2682。
(3) (13aS, 14R)-14-cyclohexylamino-3,6, western pyridine (G-2) in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles
Figure GPA00001137007000222
The above 125mg intermediate 2 (G-4) that obtains is dissolved in the tetrahydrofuran (THF) of 8mL, adds tetrahydrochysene lithium aluminium 60mg under the protection of inert gas, shading back flow reaction 2h; then reaction solution is cooled to room temperature; slowly drip the mixed solution of tetrahydrofuran (THF)/water (volume ratio 1: 1) to there not being bubble to overflow, in mixed solution, add methylene dichloride 8mL then, mixed solution is filtered; filter residue is washed with methylene dichloride; the merging filtrate evaporate to dryness, product is oily, drips dilute hydrochloric acid to product in this product and dissolves; filter; filtrate is transferred pH to 8 with 10% NaOH solution, and product is solid-state separates out, and product is leached; a small amount of washing; place moisture eliminator vacuum-drying under the room temperature, obtain product (13aS, 14R)-14-cyclohexylamino-3; 6; western pyridine (G-2) 96mg in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles, yield 79.1%; nucleus magnetic hydrogen spectrum (500MHz, CDCl 3, 25 ℃, mark in the TMS): 8.19 (1H, d, J=9Hz), 7.19 (1H, dd, J=9Hz, 2Hz), 7.86 (1H, d, J=2Hz), 7.87 (1H, s), 7.15 (1H, s), 4.69 (1H, m), 4.43 (1H, d, J=14Hz), 3.72 (1H, d, J=14Hz), 4.10 (3H, s, MeO), 4.04 (3H, s, MeO), 4.01 (3H, s, MeO), 3.29 (1H, m), 2.72 (1H, m), 2.51 (1H, m), 2.43 (1H, m), 2.37 (1H, m), 1.93 (4H, m), 1.82 (1H, m), 1.63 (3H, m), 1.29-1.14 (4H, m), 1.01 (1H, m).HRMS(ESI)calcd?for[M+H] +C 29H 37N 2O 3461.2799，found?461.2811。
Embodiment 6:(13aS, 14R)-14-benzamido group-3,6, western pyridine (H-2) and (13aS, 14S)-14-benzamido group-3,6, western pyridine (H-1) synthesizes in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles
(1) (13aS, 14S)-14-benzamido group-3,6, in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-11-indoles western pyridine ketone (H-3) and (13aS, 14R)-14-benzamido group-3,6, western pyridine ketone (H-4) in luxuriant and rich with fragrance parallel [9, the 10-b]-11-indoles of 7-trimethoxy-9-
Figure GPA00001137007000231
Under-20 ℃ with reactant (S)-(+)-N-3; 6; the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-11, western pyridine diketone (7) 0.2g is dissolved in the 2mL methylene dichloride in the 14-indoles; add benzylamine 0.1mL under the protection of inert gas; titanium tetrachloride 0.028mL; stirring reaction 1h under this temperature rises to room temperature and reacts 24h more then, adds sherwood oil 1.5mL in reaction solution; methylene dichloride 2mL; stirred 5 minutes; filter with diatomite then, the filtrate evaporate to dryness is with a spot of methylene chloride mixed solution dissolving; adding sodium borohydride 0.1g reduces; behind the reaction 30min, in reaction solution, add saturated ammonium chloride solution 10mL termination reaction, the organic layer washing; dry; evaporate to dryness; separate with silica gel column chromatography then; moving phase is methylene chloride (volume ratio 40: 1), successively obtains two intermediates, is respectively intermediate 1 (13aS; 14S)-14-benzamido group-3; western pyridine ketone (H-3) in the luxuriant and rich with fragrance a pair of horses going side by side of 6,7-trimethoxy-9-[9,10-b]-11-indoles; be 95mg, yield 38.5%.Intermediate 2 (13aS, 14R)-14-benzamido group-3,6, western pyridine ketone (H-4) in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-11-indoles is 143mg, yield 57.9%.Nucleus magnetic hydrogen spectrum (500MHz, the CDCl of intermediate 1 (H-3) 3, 25 ℃, mark in the TMS): 8.05 (1H, d, J=9.5Hz), 7.93 (2H, s), 7.28-7.19 (7H, m), 5.34 (1H, d, J=18Hz), 4.65 (1H, d, J=18Hz), 4.53 (1H, s), 3.99 (1H, m), 4.12 (3H, s, MeO), 4.06 (3H, s, MeO), 4.05 (3H, s, MeO), 3.91 (1H, d, J=12.5Hz), 3.82 (1H, d, J=12.5Hz) 2.79 (1H, m), 2.57 (2H, m), 2.31 (1H, m).Nucleus magnetic hydrogen spectrum (500MHz, the CDCl of intermediate 2 (H-4) 3, 25 ℃, mark in the TMS): 8.01 (1H, d, J=9Hz), 7.88 (1H, m), 7.89 (1H, s), 7.28-7.17 (7H, m), 5.45 (1H, d, J=16.5Hz), 4.37 (1H, d, J=16.5Hz), 4.55 (1H, d, J=6.5Hz), 4.09 (1H, m), 4.11 (3H, s, MeO), 4.06 (3H, s, MeO), 4.02 (3H, s, MeO), 3.77 (1H, d, J=12.5Hz), 3.63 (1H, d, J=12.5Hz) 2.70 (1H, m), 2.59 (2H, m), 2.17 (1H, m).
(2) (13aS, 14S)-14-benzamido group-3,6, western pyridine (H-1) in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles
Figure GPA00001137007000241
The above 95mg intermediate 1 (H-3) that obtains is dissolved in the tetrahydrofuran (THF) of 5mL, adds tetrahydrochysene lithium aluminium 50mg under the protection of inert gas, shading back flow reaction 2h; then reaction solution is cooled to room temperature; slowly drip the mixed solution of tetrahydrofuran (THF)/water (1: 1) to there not being bubble to overflow, in mixed solution, add methylene dichloride 5mL then, mixed solution is filtered; filter residue is washed with methylene dichloride; the merging filtrate evaporate to dryness, product is oily, drips dilute hydrochloric acid to product in this product and dissolves; filter; filtrate is transferred pH to 8 with 10% NaOH solution, and product is solid-state separates out, and product is leached; a small amount of washing; place moisture eliminator vacuum-drying under the room temperature, obtain product (13aS, 14S)-14-benzamido group-3; 6; western pyridine (H-1) 76mg in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles, 82.4%; nucleus magnetic hydrogen spectrum (500MHz, CDCl 3, 25 ℃, mark in the TMS): 8.06 (1H, d, J=9.0Hz), 7.26 (1H, dd, J=9.0Hz, 2Hz), 7.91 (1H, d, J=2Hz), 7.92 (1H, s), 7.31 (2H, m), 7.23 (1H, m), 7.20-7.16 (3H, m), 4.68 (1H, d, J=15Hz), 3.60 (1H, d, J=15Hz), 4.44 (1H, m), 4.11 (3H, s, MeO), 4.05 (3H, s, MeO), 4.02 (3H, s, MeO), 3.50 (1H, m), 4.11 (1H, d, J=13Hz), 3.94 (1H, d, J=13Hz), 2.66 (1H, m), 2.47-2.36 (2H, m), 2.05-2.00 (2H, m), 1.92 (1H, m).HRMS(ESI)calcd?for?[M+H] +C 30H 33N 2O 3469.2486，found?469.2502。
(3) (13aS, 14R)-14-benzamido group-3,6, western pyridine (H-2) in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles
Figure GPA00001137007000242
(H-2)
The above 143mg intermediate 2 (H-4) that obtains is dissolved in the tetrahydrofuran (THF) of 8mL, adds tetrahydrochysene lithium aluminium 60mg under the protection of inert gas, shading back flow reaction 2h; then reaction solution is cooled to room temperature; slowly drip the mixed solution of tetrahydrofuran (THF)/water (volume ratio 1: 1) to there not being bubble to overflow, in mixed solution, add methylene dichloride 8mL then, mixed solution is filtered; filter residue is washed with methylene dichloride; the merging filtrate evaporate to dryness, product is oily, drips dilute hydrochloric acid to product in this product and dissolves; filter; filtrate is transferred pH to 8 with 10% NaOH solution, and product is solid-state separates out, and product is leached; a small amount of washing; place moisture eliminator vacuum-drying under the room temperature, obtain product (13aS, 14R)-14-benzamido group-3; 6; western pyridine (H-2) 116mg in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles, yield 83.5%; nucleus magnetic hydrogen spectrum (500MHz, CDCl 3, 25 ℃, mark in the TMS): 8.16 (1H, d, J=9.0Hz), 7.87 (1H, d, J=2Hz), 7.90 (1H, s), 7.25-7.16 (7H, m), 4.56 (1H, d, J=7Hz), 4.49 (1H, d, J=14.5Hz), 3.72 (1H, d, J=15Hz), 4.10 (3H, s, MeO), 4.06 (3H, s, MeO), 4.02 (3H, s, MeO), 3.37 (1H, m), 3.83 (1H, d, J=13Hz), 3.65 (1H, d, J=13Hz), 2.67 (1H, m), 2.51-2.49 (2H, m), 2.03-1.95 (3H, m).HRMS(ESI)calcd?for[M] +C 30H 32N 2O 3468.2412，found?468.2370。
Embodiment 7:(13aS, 14S)-14-amino-3,6, western pyridine (C-1) is synthetic in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles
Figure GPA00001137007000251
With reactant (13aS, 14S)-14-benzamido group-3,6, the luxuriant and rich with fragrance a pair of horses going side by side [9 of 7-trimethoxy-9-, 10-b]-indoles in western pyridine (H-1) 0.1g add in the 10mL ethanol, add concentrated hydrochloric acid 0.5mL then, add 10% Pd/C 0.1g again, catalytic hydrogenation is 24 hours under two atmospheric hydrogen pressures, take out then, with the catalyzer filtering, the filtrate evaporate to dryness, add the 5mL water dissolution, transferring pH with 10%NaOH solution then is 4, as seen has precipitation to occur, and filters, a small amount of washing, place moisture eliminator vacuum-drying under the room temperature, obtain product (13aS, 14S)-14-amino-3,6, western pyridine (C-1) 66mg in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles, yield 81%, nucleus magnetic hydrogen spectrum (500MHz, CDCl 3, 25 ℃, mark in the TMS): 8.18 (1H, d, J=9.0Hz), 7.27 (1H, dd, J=9.0Hz, 2Hz), 7.90 (1H, d, J=2Hz), 7.89 (1H, s), 7.13 (1H, s), 4.54 (1H, d, J=14.5Hz), 3.60 (1H, d, J=14.5Hz), 4.43 (1H, m), 4.10 (3H, s, MeO), 4.04 (3H, s, MeO), 4.01 (3H, s, MeO), 3.42 (1H, m), 2.62 (1H, m), 2.44 (1H, m), 2.16 (1H, m), 1.92 (3H, m).HRMS(ESI)calcd?for[M+H] +?C 23H 27N 2O 3379.2016，found?379.2021。
Embodiment 8:(13aS, 14R)-14-amino-3,6, western pyridine (C-2) is synthetic in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles
Figure GPA00001137007000261
With reactant (13aS, 14R)-14-benzamido group-3,6, the luxuriant and rich with fragrance a pair of horses going side by side [9 of 7-trimethoxy-9-, 10-b]-indoles in western pyridine (H-2) 0.1g add in the 10mL ethanol, add concentrated hydrochloric acid 0.5mL then, add 10% Pd/C 0.1g again, catalytic hydrogenation is 24 hours under two atmospheric hydrogen pressures, take out then, with the catalyzer filtering, the filtrate evaporate to dryness, add the 5mL water dissolution, transferring pH with 10%NaOH solution then is 4, as seen has precipitation to occur, and filters, a small amount of washing, place moisture eliminator vacuum-drying under the room temperature, obtain product (13aS, 14R)-14-amino-3,6, western pyridine (C-2) 72mg in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles, yield 83%, nucleus magnetic hydrogen spectrum (500MHz, CDCl 3, 25 ℃, mark in the TMS): 8.18 (1H, d, J=9.0Hz), 7.22 (1H, dd, J=9.0Hz, 2.0Hz), 7.89 (1H, d, J=2.0Hz), 7.90 (1H, s), 7.15 (1H, s), 4.53 (1H, d, J=7Hz), 4.49 (1H, d, J=14.5Hz), 3.72 (1H, d, J=14.5Hz), 4.10 (3H, s, MeO), 4.05 (3H, s, MeO), 4.01 (3H, s, MeO), 3.38 (1H, m), 2.55 (1H, m), 2.46 (1H, m), 2.32 (1H, m), 2.04-1.87 (3H, m).HRMS(ESI)calcd?for[M+H] +C 23H 27N 2O 3379.2016，found?379.2019。
Embodiment 9:(13aS, 14R)-14-cyclopropyl amino-3,6, western pyridine (I-2) and (13aS, 14S)-14-cyclopropyl amino-3,6, western pyridine (I-1) synthesizes in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles
(1) (13aS, 14S)-14-cyclopropyl amino-3,6, in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-11-indoles western pyridine ketone (I-3) and (13aS, 14R)-14-cyclopropyl amino-3,6, western pyridine ketone (I-4) in luxuriant and rich with fragrance parallel [9, the 10-b]-11-indoles of 7-trimethoxy-9-
Under-20 ℃ with reactant (S)-(+)-N-3; 6; the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-11, western pyridine diketone (7) 0.2g is dissolved in the 2mL methylene dichloride in the 14-indoles; add cyclopropylamine 0.1mL under the protection of inert gas; titanium tetrachloride 0.028mL; stirring reaction 1h under this temperature rises to room temperature and reacts 24h more then, adds sherwood oil 1.5mL in reaction solution; methylene dichloride 2mL; stirred 5 minutes; filter with diatomite then, the filtrate evaporate to dryness is with a spot of methylene chloride mixed solution dissolving; adding sodium borohydride 0.1g reduces; behind the reaction 30min, in reaction solution, add saturated ammonium chloride solution 10mL termination reaction, the organic layer washing; dry; evaporate to dryness; separate with silica gel column chromatography then; moving phase is methylene chloride (volume ratio 50: 1), successively obtains two intermediates, is respectively intermediate 1 (13aS; 14S)-14-cyclopropyl amino-3; western pyridine ketone (I-3) in the luxuriant and rich with fragrance a pair of horses going side by side of 6,7-trimethoxy-9-[9,10-b]-11-indoles; be 55mg, yield 24.9%.Intermediate 2 (13aS, 14R)-14-cyclopropyl amino-3,6, western pyridine ketone (I-4) in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-11-indoles is 107mg, yield 48.4%.Nucleus magnetic hydrogen spectrum (500MHz, the CDCl of intermediate 1 (I-3) 3, 25 ℃, mark in the TMS): 8.35 (1H, d, J=9Hz), 7.25 (1H, dd, J=9Hz, 2.5Hz), 7.93 (1H, d, J=2.5Hz), 7.94 (1H, s), 7.21 (1H, s), 5.29 (1H, d, J=17.5Hz), 4.65 (1H, d, J=17.5Hz), 4.52 (1H, s), 3.97 (1H, m), 4.12 (3H, s, MeO), 4.06 (3H, s, MeO), 4.03 (3H, s, MeO), 2.63 (1H, m), 2.52 (1H, m), 2.43 (1H, m), 2.24 (1H, m), 2.08 (1H, m), 0.50-0.31 (4H, m).Nucleus magnetic hydrogen spectrum (500MHz, the CDCl of intermediate 2 (I-4) 3, 25 ℃, mark in the TMS): 7.98 (1H, d, J=9Hz), 7.23 (1H, dd, J=9Hz, 2Hz), 7.88 (1H, d, J=2Hz), 7.89 (1H, s), 7.22 (1H, s), 5.43 (1H, d, J=16.5Hz), 4.36 (1H, d, J=16.5Hz), 4.54 (1H, d, J=4.5Hz), 4.12 (1H, m), 4.11 (3H, s, MeO), 4.06 (3H, s, MeO), 4.02 (3H, s, MeO), 2.77 (1H, m), 2.57 (2H, m), 2.29 (1H, m), 2.18 (1H, m), 0.52-0.44 (4H, m).
(2) (13aS, 14S)-14-cyclopropyl amino-3,6, western pyridine (I-1) in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles
Figure GPA00001137007000271
The above 55mg intermediate 1 (I-3) that obtains is dissolved in the tetrahydrofuran (THF) of 5mL, adds tetrahydrochysene lithium aluminium 50mg under the protection of inert gas, shading back flow reaction 2h; then reaction solution is cooled to room temperature; slowly drip the mixed solution of tetrahydrofuran (THF)/water (volume ratio 1: 1) to there not being bubble to overflow, in mixed solution, add methylene dichloride 5mL then, mixed solution is filtered; filter residue is washed with methylene dichloride; the merging filtrate evaporate to dryness, product is oily, drips dilute hydrochloric acid to product in this product and dissolves; filter; filtrate is transferred pH to 8 with 10% NaOH solution, and product is solid-state separates out, and product is leached; a small amount of washing; place moisture eliminator vacuum-drying under the room temperature, obtain product (13aS, 14S)-14-cyclopropyl amino-3; 6; western pyridine (I-1) 45mg in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles, 84.6%; nucleus magnetic hydrogen spectrum (500MHz, CDCl 3, 25 ℃, mark in the TMS): 8.22 (1H, d, J=9.0Hz), 7.25 (1H, dd, J=9.0Hz, 2Hz), 7.91 (1H, d, J=2Hz), 7.92 (1H, s), 7.18 (1H, s), 4.72 (1H, d, J=14.5Hz), 3.65 (1H, d, J=4.5Hz), 4.51 (1H, m), 4.11 (3H, s, MeO), 4.06 (3H, s, MeO), 4.02 (3H, s, MeO), 3.52 (1H, m), 3.34 (1H, m), 2.81 (1H, m), 2.42 (1H, m), 2.32 (1H, m), 1.98 (1H, m), 1.89 (2H, m), 0.52-0.29 (4H, m).
(3) (13aS, 14R)-14-cyclopropyl amino-3,6, western pyridine (I-2) in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles
Figure GPA00001137007000281
The above 107mg intermediate 2 (I-4) that obtains is dissolved in the tetrahydrofuran (THF) of 8mL, adds tetrahydrochysene lithium aluminium 60mg under the protection of inert gas, shading back flow reaction 2h; then reaction solution is cooled to room temperature; slowly drip the mixed solution of tetrahydrofuran (THF)/water (volume ratio 1: 1) to there not being bubble to overflow, in mixed solution, add methylene dichloride 8mL then, mixed solution is filtered; filter residue is washed with methylene dichloride; the merging filtrate evaporate to dryness, product is oily, drips dilute hydrochloric acid to product in this product and dissolves; filter; filtrate is transferred pH to 8 with 10% NaOH solution, and product is solid-state separates out, and product is leached; a small amount of washing; place moisture eliminator vacuum-drying under the room temperature, obtain product (13aS, 14R)-14-cyclopropyl amino-3; 6; western pyridine (I-2) 76mg in the luxuriant and rich with fragrance a pair of horses going side by side of 7-trimethoxy-9-[9,10-b]-indoles, yield 73.4%; nucleus magnetic hydrogen spectrum (500MHz, CDCl 3, 25 ℃, mark in the TMS): 8.17 (1H, d, J=9.0Hz), 7.20 (1H, dd, J=9.0Hz, 2Hz), 7.89 (1H, d, J=2Hz), 7.91 (1H, s), 7.15 (1H, s), 4.65 (1H, m), 4.52 (1H, d, J=14Hz), 3.80 (1H, d, J=14Hz), 4.10 (3H, s, MeO), 4.05 (3H, s, MeO), 4.02 (3H, s, MeO), 3.34 (1H, m), 3.21 (1H, m), 2.57 (2H, m), 2.50 (1H, m), 2.05 (3H, m), 0.56-0.41 (4H, m).
Pharmacological testing
Experimental example 1: the mensuration of anti tumor activity in vitro (mtt assay)
In order to measure the anti tumor activity in vitro of The compounds of this invention, the compound for preparing in the embodiment of the invention to be measured, its experimental procedure is:
1. cultivate the tumour cell of normal growth, with 1 * 10 4Cell/mL is inoculated into (every hole 100 μ L) in 96 orifice plates, at 37 ℃, and 5%CO 2Cultivated 24 hours in the incubator.
2. add tested compound respectively, at 5%CO 2, cultivated 5 days in the humidity incubator fully.
3. reject nutrient solution, every hole adds 0.04%MTT 100 μ L, cultivates 4 hours under the similarity condition.
4. the reject nutrient solution adds DMSO (every hole 150 μ L), mixes the back in mensuration wavelength 570nm, reference wavelength 450nm, and colorimetric recording light optical density, the computerized compound is to the inhibiting rate of growth of tumour cell.
Result of experiment is as shown in Table 1 and Table 2:
Result's (taxol contrast) that the synthetic product MTT of table 1 13a-(S)-deoxidation tylophorinine (CAT) measures
Figure GPA00001137007000291
Annotate: Sw1990: human pancreas's adenocarcinoma cell; Hela: human cervical carcinoma cell; Bel-7402: human liver cancer cell; A549:
Human lung adenocarcinoma cell; Panc-1: human pancreatic cancer cell; Capan-2: human pancreatic cancer cell.
Results suggest is compared in reference substance, and the synthetic product of 13a-(S)-deoxidation tylophorinine have notable antitumor activity equally.
The MTT measurement result of table 2 13a-(S)-14 substitutive derivatives of deoxidation tylophorinine part
Figure GPA00001137007000292
Figure GPA00001137007000293
Annotate: HCT-8: human colon cancer cell; Bel-7402: human liver cancer cell; BGC-823: gastric carcinoma cells; A549: human lung adenocarcinoma cell; A2780: Proliferation of Human Ovarian Cell.
From above results of screening as can be seen,
14 amido substitutive derivatives in human colon cancer cell, human liver cancer cell, gastric carcinoma cells, human lung adenocarcinoma cell, the Proliferation of Human Ovarian Cell at least 2 kinds have activity, wherein majority of compounds all has activity to 4 kinds of cancer cells.
14 methoxyl group substitutive derivatives all have activity to human colon cancer cell, human liver cancer cell, gastric carcinoma cells, Proliferation of Human Ovarian Cell.

Claims (3)

1. the preparation method of formula (I) compound,
Figure FSB00001080243500011
Wherein, R is selected from-NR 1R 2Or-OR 3
R 1And R 2Independently be selected from hydrogen, replacement or unsubstituted C 1-10Straight chain and branched-chain alkyl, replacement or unsubstituted C 3-7Cycloalkyl, replacement or unsubstituted phenyl;
R 3Be selected from unsubstituted C 1-10Straight chain and branched-chain alkyl;
Substituting group is selected from hydroxyl, sulfydryl, amino-NH 2, C 1-6Amino, phenyl that alkyl replaces;
It is characterized in that:
(1) as R is-NR 1R 2, do not comprise that R is NH 2The time:
With the 14-position carbonyl of formula 7 with replace amine through compound shown in the reductive amination process production 10, chromatographic separation diastereomer isomer, the 11-position amidocarbonylation that reduces respectively gets compound shown in the general formula (I):
Figure FSB00001080243500012
：
(2) as R be-NH 2The time:
With the 14-position carbonyl of formula 7 and benzylamine through compound shown in the reductive amination process production 9, chromatographic separation diastereomer isomer, the 11-position amidocarbonylation that reduces respectively gets compound shown in the general formula (I), wherein R1 is selected from H, R2 is selected from benzyl, then compound is generated compound shown in the general formula (I) through hydrogenation respectively, wherein R1 and R2 all are selected from hydrogen:
Figure FSB00001080243500022
(3) as R be-OR 3The time:
Become hydroxyl to obtain compound shown in the formula 8 the 14-position carbonyl reduction of formula 7, with compound shown in the 14-position hydroxyl of formula 8 and the haloalkane generation substitution reaction production 11, chromatographic separation diastereomer isomer, the 11-position carbonyl that reduces respectively gets compound shown in the general formula (I):
Figure FSB00001080243500032
Figure FSB00001080243500041
2. preparation method as claimed in claim 1 is characterized in that, when R is-NR 1R 2The time: the catalyzer that the 14-position carbonyl of formula 7 is carried out reduction amination is titanium tetrachloride, and reaction solvent is methylene dichloride.
3. want 1 described preparation method as right, it is characterized in that, when R is-OR 3The time: be sodium hydride with the 14-position hydroxyl of formula 8 and the catalyzer of haloalkane generation substitution reaction, reaction solvent is tetrahydrofuran (THF).
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